1. Field of the Invention
The present invention relates generally to the fields of neurology, immunology and protein chemistry. More specifically, the present invention relates to a novel methods of treating auto-immune diseases using type one interferons.
2. Description of the Related Art
Acute experimental autoimmune encephalomyelitis [EAE] is a T cell mediated inflammatory autoimmune process of the central nervous system which resembles the human disease multiple sclerosis. CR-EAE, a chronic inflammatory autoimmune process of the central nervous system that resembles human multiple sclerosis [MS] both in its pathological and clinical expression, provides a model to assess interventions to alter the course of a human autoimmune disease. Myelin basic protein [MBP] is an important neuroantigen in the pathogenesis of this disease. CR-EAE in SJL/J mice can b e adoptively transferred following the intravenous injection of an MBP peptide 89-100 specific T cell line. Coculture of MBP peptide 91-103 specific T cells with chemically crosslinked peptide renders the T cells tolerant to MBP in CR-EAE in the SJL/J mouse.
Parenteral, e.g., IV administration of natural rat interferon [105 units] partially suppresses acute EAE in male Lewis rats and inhibits passive hyperacute localized EAE when administered on the same day of immunogen inoculation. Other parenterally administered cytokines such as TGF-β can decrease clinical disease and inflammation in brain and spinal cord in EAE. Parenterally administered natural human IFN-α can decrease T cell function and T cell dependent antibody production in humans. Orally administered natural human IFN-α can prevent experimental development of viral and parasitic infections in animals. Acute EAE provides a model to demonstrate the ability of orally administered immunoactive substances to influence the course of an autoimmune disease.
Human IFN-α is an immunoactive protein that can b e orally administered at low doses in the treatment of viral disease in animals. Human IFN-β, another type 1 interferon, augments suppressor cell function in vitro in progressive MS and rat IFN-β decreases the severity of symptoms in rat EAE. In view of the immunoregulatory and anti-viral properties of the type 1 interferons, its response and production has been assessed in autoimmune diseases. Inactive rheumatoid arthritis is marked by augmented [2′-5′] oligoadenylate synthetase [OAS], a readily assayed measurement of type 1 interferon activity, in peripheral blood leucocytes secondary to an IFN-α/β stimulus; active rheumatoid arthritis exhibited a significantly reduced IFN-α/β production compared to normal donors. Other autoimmune diseases, such as psoriasis and atopic dermatitis, also showed decreased interferon production. Peripheral blood lymphocytes in patients with MS show a similar ineffective production of type 1 interferons in response to viral or mitogenic stimulus which parallels the severity of the disease. Natural killer [NK] cell activity is deficient in MS, which is correlated with disease severity, and can be normalized with IFN-α treatment.
The reported abnormalities of production or response to type 1 interferon in autoimmune diseases have prompted several small pilot studies using type 1 interferons as therapeutic agents in MS. These studies used systemic administered type 1 interferon in doses of 1 million units or more daily without significant clinical improvement. A study of parenterally administered IFN-β in relapsing-remitting MS suggests that 1.6-8 million units of IFN-β s.c., three times per week, can decrease relapses by 40-50% and decrease brain inflammation as assessed by serial MRI.
Additionally, rheumatoid arthritis (RA) is a common chronic disorder involving the synovial membranes of multiple joints that is considered by most to be an autoimmune disease. Within joints of patients with rheumatoid disease, chronic (lymphocyte mediated) or acute (lymphocyte and polymorph mediated) tissue inflammation are the predominant mechanisms leading to tissue changes in synovial joints (Cruikshank, 1954). In light of th e research performed in conjunction with the present series of applications, an open label phase I study was performed with ingested IFN-α to determine the safety, clinical effects on joint disease, and potential modulation of proinflammatory cytokine secretion in subjects with RA.
Insulin-dependent diabetes mellitus (IDDM) is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic b cell. In the United States, the prevalence of IDDM by age 20 years is 0.26% and lifetime prevalence approaches 0.40%; thus approximately one million Americans have IDDM. Histologic studies suggest that an 80% reduction in the volume of b cells is required to induce symptomatic IDDM. The nonobese diabetic (NOD) mouse is a model of the human autoimmune disease. Many key features of human IDDM are reflected in the NOD mouse model; the development of insulinitis with infiltration of lymphocytes into the pancreatic islets of Langerhans that are selectively cytotoxic to the insulin producing b cells; the dependence of disease pathogenesis by T cells; transmission of IDDM by hematopoietic cells in bone marrow.
The NOD mouse model is mechanistically analogous to the EAE animal model because they are both presumed to be T cell subset mediated, dependent on restriction elements and inflammatory cytokines for disease expression. Although neither acute or chronic EAE have exact parallels to the NOD model, their similarities suggest that interventions successful in EAE can have therapeutic efficacy in the NOD mouse. Both IDDM and EAE can be induced by T cells, primarily one of the two types of helper T cells—T helper cells type 1 (Th1) which produce pro-inflammatory cytokines such as IL-2, IFN-γ or TNF-α. In contrast, administration or up-regulation of the Th2-associated cytokines IL-4 and IL-10 is beneficial and can ameliorate autoimmune disease.
The prior art is deficient in the lack of effective means of treating auto-immune diseases by oral administration of cytokines, such as type one interferons. The present invention fulfills this longstanding need and desire in the art.